The Washington Blade; Friday, January 31, 1997
Lisa Keen

Following the International Conference on AIDS in Vancouver last July, most experts seemed comfortable with the idea that patients could reasonably take a more "conservative" approach -- wait until their CD4 counts dropped below 500 or their viral loads went above 30,000, then start on a two-drug regimen of nucleoside analogs (AZT, ddI, ddC, d4T, or 3TC).

Researchers and AIDS activists debated the merits of those two approaches as recently as November and December when the National Institutes of Health convened panels of experts to come up with recommendations to help doctors and patients decide how best to treat HIV infection. At that point, a large number of experts were already recommending the aggressive "hit early and hard" strategy, and a large number of activists were offering strong reasons for the more conservative "wait and see" approach.

Those for aggressive early therapy note that drugs have a better chance of eradicating HIV from the body if they can stop the virus before it penetrates a large number of non-blood reservoirs in the body -- such as the central nervous system -- and before the virus can mutate into numerous forms to escape any drug therapy.

Those who argue for the more conservative approach note that most patients have had only about a year's experience on protease inhibitors and that their long-term "durability" in stopping the AIDS virus from replicating has not yet been proven. And patients who use protease inhibitors now may not been able to switch to other therapies later if the virus mutates around the protease drugs.

Eradication

"If we knew we could wipe out the virus, we would have good reason to go with treating everybody," explained AIDS activist Mark Harrington last fall, "but we won't know the answer to that question" for at least a year maybe more.

Harrington, an activist with Treatment Action Group, made his observation in December after serving as a member of the National Institutes of Health panels, most of which were open to the public. He said that "privately, most researchers say they don't think it's possible" to eradicate HIV completely from the body. But while that hope of complete eradication was clearly tempered at last week's conference, the Fourth Conference on Retroviruses and Opportunistic Infections, it was by no means abandoned.

On the first day of the five-day conference, researcher David Ho, who has been the lead promoter of the "hit early, hit hard" strategy, last Wednesday conceded that his hopes in July of proving eradication by the end of 1996 had been "premature." He presented new data showing that it will take at least two to two and a half years for the AIDS virus to decay out of "known compartments" in the body. And that is assuming the "hit early, hit hard" strategy is, in fact, stopping the virus from replicating. So far, it appears to be stopping HIV replication. But doctors can't be certain because there is no test currently available to measure viral load at any number fewer than 100 to 500 particles per milliliter. (Roche is said to be developing a more sensitive test, which is in use by some researchers, but even it will go only as low as 20 particles per milliliter.)

Expanding somewhat on Ho's report, Marty Markowitz, Ho's colleague at the Aaron Diamond AIDS Research Center in New York, said Sunday that all patients in the Diamond Center's "hit early, hit hard" trial who have been compliant with their triple-drug therapy still have kept their viral loads below 500 for as long as 18 months in some cases. Seven patients have been taking a Ritonavir-AZT-3TC combination for between 11 and 18 months, and 11 patients have been taking an Indinavir-AZT-3TC combination for between four and nine months. And there, again, lies the rub: Time. The triple-drug combinations using a protease inhibitor have not been proven beyond 18 months and -- assuming it can be done -- it takes at least 24 months, probably 30 or 36 months, for the virus to be eliminated from the body.

Restoration

While the AIDS virus and drugs to attack the AIDS virus have always been a major focus of these scientific conferences, a growing area of focus in recent months has been the patient's immune system. If the virus can be eliminated completely from the body, what can a patient do to repair his or her damaged immune system so as not to remain forever vulnerable to diseases?

Some argue for early therapy, saying it can help prevent damage. Others hold out hope that some immune booster-type therapies may help mitigate the damage. Research first presented last fall suggested that the immune system is irreparably damaged once a patient's number of CD4 cells (the cells which fight off infections) drops below 50. That research, and studies presented during last week's conference, indicate that while the AIDS virus can kill off CD4 cells that have a "memory" to attack specific diseases, the virus appears to more quickly kill off the more broadly useful CD4 cell -- a "naive" cell -- first.

Once treatment begins to help a patient replenish his or her supply of CD4 cells, the immune systems appears to reproduce only what cells are still left in the system.

A poster from the University of Rochester, studying a triple-drug combination of Indinavir-AZT-3TC in 24 patients, found the rise in CD4 cells consisted "almost completely" of memory cells after one month. But a presentation from France, studying Ritonavir-AZT-ddC in 20 patients, suggested that the number of naive cells might begin to increase after about six months.

A third report, from the National Institutes of Allergies and Infectious Diseases, studying 39 patients taking Indinavir, found that the drug increased the number of naive cells "only if they were present prior to initiation of therapy." Those patients taking interleuken-II had an increase in both memory and naive cells after 12 months, said the presenter.

The issue is important because if HIV can be eradicated from the body, the patients must still have a strong immune system to survive other diseases in their lifetimes. And it's important for another reason, too. Currently, once a patient's CD4 count drops below about 200, doctors recommend he or she begin taking a variety of additional drugs to help ward off opportunistic infections. This recommendation adds another slew of pills to an already burdensome regimen of pill-taking. So the CD4 reports last week added more information geared toward answering a question that began emerging late last year: If triple-drug therapies help restore a patient's CD4 count to previously high levels, can the patient stop taking at least those drugs used to help prevent opportunistic infections?

The answer at this point, as NIAID researcher Mark Connors seemed to see it, is that patients should be "cautioned against" doing that.

Mutation

While the complications around virus eradication and immune restoration are already posing incredibly complex and difficult decisions for patients and doctors to wrestle with, new information last week also promised to throw yet another wrench into the works. It was perhaps best illustrated by a report presented last Thursday in which researchers noted that patients in rural Iowa who had never been treated with any AIDS drug are infected with strains of the virus that already contain mutations that can lead to the virus being able to resist many AIDS drugs, including the three protease inhibitors currently approved for marketing.

The problem is not new. As University of California-San Diego researcher Douglas Richman noted in a presentation Saturday, doctors were facing this kind of pre-treatment drug resistance with tuberculosis in the 1950s. And it's not new to AIDS treatment either. A few years after the initiation of treatment with AZT, researchers found that some new patients were being infected with a form of the virus already resistant to AZT.

The Iowa researcher who presented the report also noted that, despite these mutations, his patients did seem to be responding well to triple-drug regimens which included protease inhibitors. (It seems that one or two such mutations do not translate into immediate resistance but do mean that the virus will likely reach resistance sooner, after about four to six mutations.)

But the problem does, nevertheless, have implications for a patient's decision about which drugs to start taking. There are tests in existence which can identify these kinds of details about a patient's virus, but these tests are complicated and expensive and not available in the standard clinical setting, said Richman.

One response to this mutation problem, suggested Richman, is to minimize or prevent the emergence of these mutations by starting treatment as soon as possible and hitting as hard as possible -- the aggressive strategy of going for "complete suppression."

But, as Richman conceded, "complete suppression is an assumption."

The NIH panel of experts is not expected to finalize its revised recommendations for treatment until sometime in March. In the meantime, the consensus at last week's conference seemed to favor "hit early, hit hard." But even advocates of this aggressive strategy broke it down into two choices:

--If researchers find it is not "feasible" or possible to eradicate HIV from the body, then doctors should treat HIV like they do high blood pressure -- using a conservative approach of prescribing drugs as needed with an expectation of treating the patient forever. With this strategy, said AIDS researcher Ann Collier on Saturday, most patients will probably want to initiate therapy with three nucleoside analogs and, when that begins to fail, switch to a protease inhibitor and two new nucleoside analogs.

--If eradication is feasible and possible, then doctors will probably want to treat HIV like they do tuberculosis -- using an aggressive approach of heavy-hitting drug regimens initiated as early as possible to eliminate the disease. Collier suggested this might typically be regimen of one protease inhibitor plus two nucleoside analogs.

But whenever one chooses to start whatever therapy, the key will still be to drop viral load as much as possible. Viral load guru John Mellors of the University of Pittsburgh reported Saturday that data is now showing that "the further the viral load drops, the longer it lasts."

As common sense would dictate, if the viral load can be dropped to zero, it lasts forever. And as Ho and others predict, it will be at least a year before scientists will know if they can achieve that big zero.

Next week: Details on combination study results.

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